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Spinal tuberculosis infection induces osteopenia by reducing the migration and osteogenesis of bone marrow mesenchymal stem cells

ABSTRACT: Objectives: Bone marrow mesenchymal stem cells (BMSC) play an important role in osteogenesis. However, the role of BMSC in osteopenia in spinal tuberculosis (STB) patients is unclear. Methods: Bone mineral density (BMD) of 53 STB patients and 55 controls was measured. The migration and osteogenesis of BMSC were assessed by wound healing assays and alizarin red staining, and osteoclast marker expression was measured. RNA-seq was performed on BMSC and the enriched signaling pathways were verified. Results:BMD of STB patients was significantly decreased and BMSC migration and osteogenesis were significantly reduced. After verification, we found that the B-cell receptor signaling pathway, tuberculosis, osteoclast differentiation, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were affected.And of these pathways, the B-cell receptor signaling, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were not previously known to be involved in osteopenia. The MAPK signaling pathway and ECM-receptor interactions were correlated with STB prognosis. Conclusion: STB infection can significantly reduce BMSC migration and osteogenesis, decreasing BMD. This process is regulated by multiple pathways and is associated with STB prognosis. Our study suggests that reduced BMSC migration and osteogenesis play important roles in osteopenia in STB patients, and BMSC may be a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222013 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.

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Spinal tuberculosis infection induces osteopenia by reducing the migration and osteogenesis of bone marrow mesenchymal stem cells

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